DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed March 4, 2026, has been received and entered.
Claims 2, 3, 6, 16-34, and 39 are canceled.
Claims 1, 4, 5, 7-15, 35-38, 40, and 41 are pending. Claim 15 is withdrawn.
Claims 1, 4, 5, 7-14, 35-38, 40, and 41 are examined on the merits.
Claim Objections
Claims 1, 4, 5, 7-12, 40, and 41 are objected to because of the following informalities:
Claim 1 is objected to because a hyphen is missing between the words “thiol” and “containing” in the recitation “thiol containing” in the second-to-last line. Claim 1 should recite “thiol-containing” in the second-to-last line. Since claim 1 is objected to, then its dependent claims, claims 4, 5, 7-12, 40, and 41, are objected to.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 40 and 41 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 40 and 41 are rendered indefinite by the recitation “the mucolytic agent.” It is unclear whether it is referring to (a) the thiol-containing mucolytic agent of parent claim 1, or (b) the mucolytic agent of parent claim 8 which is a further therapeutically effective agent that is further co-administered (i.e., co-administered in addition to administering the microspheres to the patient). For the purpose of applying prior art, claims 40 and 41 are being interpreted as reciting the thiol-containing mucolytic agent of the microspheres (i.e., the thiol-containing mucolytic agent of parent claim 1).
Notice Re: Prior Art Available Under Both Pre-AIA and AIA
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Morris (US 2015/0343035. Previously cited) in view of Sakamoto (J. Hep. Bil. Pancr. Surg. 1997. 4: 157-162. Previously cited), Muller (International Journal of Oncology. 2016. 48: 2025-2034. Listed on IDS filed 5/18/22), and Ashrafi (US 2014/0030350. Previously cited).
NOTE: Morris is the published application of 14/649,518 which issued as US 11,369,666. A nonstatutory double patenting rejection is set forth below over US 11,369,666.
Morris discloses compositions for the treatment of diseases involving mucin, specifically for the treatment of mucin-secreting cancers (paragraph [0001]). The composition of Morris comprises one or more compounds in bromelain and at least one mucolytic agent, or metabolite(s), pharmaceutically acceptable salt(s), solvate(s), or prodrug(s) of each of the one or more compounds in bromelain and the at least one mucolytic agent (claim 1 of Morris). Bromelain is directed to a ‘mucin-affecting protease.’
For a method for the treatment of diseases involving mucin, the method comprises administering a therapeutically effective amount of the composition to a patient in need thereof (claim 14 of Morris). Thus, when the disease involving mucin is a mucin-secreting cancer (paragraphs [0001] and [0027]), then Morris meets limitations of the claimed method in that it is directed to a method for the treatment of a mucin-producing cancer (mucin-secreting cancer), the method comprising administering to a patient a therapeutically effective amount of a composition containing a mucin-affected protease (bromelain).
Morris differs from the claimed invention in that Morris does not expressly disclose that: (a) the composition that is administered is directed to microspheres containing the mucin-affecting protease (bromelain) loaded therein, wherein the microspheres have a diameter of between 60 and 120 micrometers and are adapted to elute the mucin-affecting protease in a sustained manner following administration, and wherein the administration is intra-arterially; (b) the microspheres are adapted to elute the mucin-affecting protease in a sustained manner over a period of time of between 5 hours and 120 hours following administration; and (c) the microspheres consist of a hydrogel containing a solution comprising the mucin-affecting protease (bromelain). Morris further differs from the claimed invention in that Morris does not expressly disclose that the mucin-producing cancer (mucin-secreting cancer) that is treated is primary or secondary liver cancer (elected species of instant claim 14).
Morris teaches that their composition may be in a form suitable for administration by injection and by oral administration such as capsules, for example (paragraph [0071]). When used in capsule form, the capsules may be coated with compounds which delay disintegration (paragraph [0073]). Also, Morris recognizes biodegradable microspheres as a suitable adjuvant included in their composition (paragraph [0085]).
Sakamoto discloses cholangiocarcinomas that produce clinically recognizable mucin, known as mucin-producing cholangiocarcinoma (abstract; page 157, first paragraph). Sakamoto investigated the clinicopathologic features of tumors in ten patients with mucin-producing cholangiocarcinoma (page 157, first paragraph). The mucin-producing cholangiocarcinoma tumors were classified into three types, including an intermediate type which was characterized by large cystic lesions and solid tumors that invaded the liver parenchyma (page 158, right column, first paragraph).
Muller discusses cholangiocarcinoma (CC), indicating that it is a primary liver tumor (page 2025, right column, first paragraph). Thus cholangiocarcinoma is directed to a primary liver cancer. Muller found that bromelain has potent anti-tumor activity against cholangiocarcinoma (page 2031, left column).
Ashrafi discloses microparticles comprising a gel body, wherein the gel body comprises a synthetic polymer and a drug, the microparticles have an average diameter in the range of 40 to 1500 micrometers, and the polymer is in the form of a hydrogel (paragraph [0016]). The microparticles may have any shape, and are preferably microspheres (paragraph [0032]). The diameter range of 40 to 1500 micrometers overlaps with the diameter range of instant claim 13, thereby rendering obvious the diameter limitation of instant claim 13.
Ashrafi teaches that their microparticles are for use in a method of treatment of a tumor (paragraph [0020]). Any drug which can be incorporated into the microparticles of the Ashrafi invention may find utility in their invention (paragraph [0050]). Examples of the drug include anti-tumor drugs and enzymes (paragraph [0050]). Preferred drugs are antineoplastic drugs and have chemotherapeutic properties, so they may be used in anti-tumor therapy (paragraph [0050]). Ashrafi also discloses a novel drug delivery system useful in the chemoembolotherapy of solid tumors in which the rate of drug release from the microparticles is altered when the tumor becomes hypoxic, leading to an increased release of drug as the disulfide cross-links cleave with the reductive environment of the tumor (paragraph [0021]). In particular, Ashrafi speaks of a composition which is administered to a patient in need of embolotherapy having a solid tumor, for instance a hepatocellular carcinoma, as an aqueous suspension of swollen particles containing absorbed drug (paragraph [0066]). Given the rate of drug release from the microparticles when used in chemoembolotherapy of solid tumors, then Ashrafi discloses microspheres that are adapted to elute the drug in a sustained manner following administration, meeting a claimed limitation.
Further still, Ashrafi discloses that the therapeutic active (drug) may be incorporated into the polymer matrix of the microparticles by a variety of techniques (paragraph [0064]). The active may be loaded into the polymer after it has been cross-linked (paragraph [0064]). For instance, particulate dried polymer may be swollen into a solution of therapeutic active (paragraph [0064]). Merely contacting swollen particles suspended in a continuous liquid vehicle with a solution of drug over an extended period results in the drug becoming absorbed into the body of the particles (paragraph [0064]). The microspheres of Ashrafi resulting from loading a drug into the microspheres by suspending the microspheres (which are a hydrogel) in a solution comprising the drug are directed to microspheres consisting of a hydrogel and a solution comprising the drug.
Additionally, Example 16 of Ashrafi investigated the biocompatibility of non-drug loaded microparticles with human liver cells (paragraph [0185]). Their experiment in Example 16 showed that the HEP G2 cells survived and replicated during the incubation period in the presence of the non-drug loaded microspheres, demonstrating that the microspheres are biocompatible and have no cytotoxic effect (paragraph [0185]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill to treat mucin-producing cholangiocarcinoma, which is a primary liver cancer, with the method of Morris. One of ordinary skill in the art would have been motivated to treat mucin-producing cholangiocarcinoma with the method of Morris since mucin-producing cholangiocarcinoma (taught in Sakamoto) is directed to a mucin-secreting cancer for which treatment is sought in patients. There would have been a reasonable expectation of treating mucin-producing cholangiocarcinoma since it is a mucin-secreting cancer (thus directed to a disease that Morris treats) and since Muller indicates that bromelain, which is one agent administered in the method of Morris, has anti-tumor activity against cholangiocarcinoma. Thus, Morris in view of Sakamoto and Muller renders obvious a method for the treatment of a mucin-producing cancer which is a primary liver cancer.
Further still, before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have provided the composition of Morris as the microparticles of Ashrafi, specifically microspheres having an average diameter in the range of 40 to 1500 micrometers (overlapping with the range of instant claim 13, thereby rendering obvious the diameter limitations), loaded with bromelain and at least one mucolytic agent by suspending hydrogel microspheres in a solution of bromelain and at least one mucolytic agent, such that a therapeutically effective amount of these microspheres is administered to the patient when performing the method rendered obvious by Morris, Sakamoto, and Muller of treating mucin-producing cholangiocarcinoma (directed to a primary liver cancer). It would have been a matter of simple substitution of one form of the composition for another that is suitable for delivery to a site in a patient (e.g. animal or human body). Since Ashrafi teaches that their microparticles are used for drug delivery in the chemoembolotherapy of solid tumors such as hepatocellular carcinoma, wherein the drug incorporated into the microparticles can be anti-tumor drugs (which the bromelain and mucolytic agents of Morris are directed to since they are used for treating mucin-secreting cancer) and enzymes (which the bromelain of Morris is directed to), then there would have been a reasonable expectation that Ashrafi’s microspheres would have been suitable for administering the bromelain and at least one mucolytic agent to the patient when performing the method rendered obvious by Morris, Sakamoto, and Muller of treating mucin-producing cholangiocarcinoma. Moreover, there would have been a reasonable expectation of treating mucin-producing cholangiocarcinoma with the microspheres of Ashrafi incorporating the bromelain and at least on mucolytic agent since Ashrafi found that their microspheres are biocompatible with human liver cells (see Example 16). Additionally, since Morris teaches that their composition may be in various forms including capsules that may be coated with compounds which delay disintegration (paragraph [0073]) and include suitable adjuvants such as biodegradable microspheres (paragraph [0085]), there would have been a reasonable expectation that the composition of Morris provided in the form of the microspheres of Ashrafi would have been suitable for administering a therapeutically effective amount of the bromelain and at least one mucolytic agent to the patient for treating mucin-producing cholangiocarcinoma (directed to a primary liver cancer). The microspheres of Ashrafi are directed to the claimed microspheres ‘adapted to elute the mucin-affecting protease in a sustained manner…following administration’ since Ashrafi discloses a rate of drug release for their microparticles (paragraph [0021]) and elution of a drug over time from their microspheres in their examples (see Figures 12A, 12B, 19, and 21). Since the references render obvious the loading of bromelain and the at least one mucolytic agent by suspending the microspheres (which are a hydrogel) in a solution of bromelain and the at least one mucolytic agent, then the references render obvious the claimed limitation ‘wherein the microspheres consist of a hydrogel containing a solution comprising the mucin-affecting protease’ of instant claim 13.
Regarding the claimed route of administration, Morris teaches that their composition can be administered to a recipient by standard routes (paragraph [0094]). For chemoembolotherapy of solid tumors, Ashrafi teaches that their invention may be used for the local targeting of tumors by delivery into the tumor vasculature via an intra-arterial route (paragraph [0021]). Ashrafi speaks of embolotherapy of a solid tumor such as a hepatocellular carcinoma (paragraph [0066]). For treating mucin-producing cholangiocarcinoma (directed to a primary liver cancer) in the method rendered obvious by Morris in view of Sakamoto, Muller, and Ashrafi, it would have been obvious to the person of ordinary skill in the art to administer the microspheres to the patient intra-arterially. One of ordinary skill in the art would have been motivated to do this because Ashrafi discloses that local targeting of their microparticles for chemoembolotherapy of solid tumors such as hepatocellular carcinoma can be obtained by delivery into the tumor vasculature via an intra-arterial route. Since mucin-producing cholangiocarcinoma can comprise a solid tumor (for instance, see the intermediate type of mucin-producing cholangiocarcinoma on page 158 of Sakamoto) and is a liver cancer and thus similar in site as hepatocellular carcinoma, then the skilled artisan would have reasonable expectation that chemoembolotherapy by intra-arterial route would have been suitable for treating mucin-producing cholangiocarcinoma.
Regarding the claimed elution time, Ashrafi discloses in their examples testing the elution of drugs from their microspheres. In Example 7, the exact amount of drug released from microspheres in two environments was calculated and shown in Figures 12A and 12B (paragraph [0153]). Figure 12A shows the elution profile up to 500 minutes, i.e. about 8 hours, and Figure 12B shows the elution profile up to about 375 minutes, i.e. about 6 hours. In Example 14, the release profile of loaded microparticles was determined and shown in Figure 19 (paragraph [0179]). Figure 19 shows the elution profile up to about 350 minutes, i.e. about 6 hours. In Example 15, the elution profile of microparticles is shown in Figure 21 (paragraph [0182]). Figure 21 shows the elution profile up to about 2750 minutes, i.e. about 46 hours. Each of these time periods of Figures 12A, 12B, 19, and 21 include periods of time falling in the range of between 5 hours and 120 hours of instant claim 1. Therefore, for performing the method rendered obvious by Morris in view of Sakamoto, Muller, and Ashrafi, it would have been obvious that the bromelain elutes from the microspheres over at least the time periods shown in Figures 12A, 12B, 19, and 21 of Ashrafi that encompass periods of time that fall in the claimed range of between 5 hours and 120 hours.
Therefore, Morris in view of Sakamoto, Muller, and Ashrafi renders obvious instant claims 13 and 14 (primary liver cancer).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 13 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,369,666 in view of Sakamoto (J. Hep. Bil. Pancr. Surg. 1997. 4: 157-162. Previously cited), Muller (International Journal of Oncology. 2016. 48: 2025-2034. Listed on IDS filed 5/18/22), and Ashrafi (US 2014/0030350. Previously cited).
Independent claims 1 and 9 of `666 meet limitations of the instant claims since they recite a method for the treatment of a mucin-producing cancer or pseudomyxoma peritonei, the method comprising administering a therapeutic effective amount of bromelain to a patient in need thereof. Bromelain is directed to a mucin-affecting protease. Though claims 1 and 9 of `666 also recite administering a therapeutically effective amount of at least one mucolytic agent which is not required by instant claims 13 and 14, this is directed to an additional limitation which is wholly encompassed by the broader scope of the instant claims.
The claims of `666 further differ from the instant claims in that they do not recite that the therapeutically effective amount of bromelain is intra-arterially administered to the patient by intra-arterially administering to the patient a therapeutically effective amount of microspheres containing bromelain (directed to the claimed ‘mucin-affecting protease’) loaded therein, wherein the microspheres have a diameter of between 60 and 120 micrometers and are adapted to elute the mucin-affecting protease in a sustained manner following administration, wherein the microspheres are adapted to elute bromelain (the mucin-affecting protease) in a sustained manner over a period of time between 5 hours and 120 hours. The claims of `666 further differ from instant claim 14 in that they do not recite that the mucin-producing cancer that is treated is primary or secondary liver cancer (elected species of instant claim 14).
Sakamoto discloses cholangiocarcinomas that produce clinically recognizable mucin, known as mucin-producing cholangiocarcinoma (abstract; page 157, first paragraph). Sakamoto investigated the clinicopathologic features of tumors in ten patients with mucin-producing cholangiocarcinoma (page 157, first paragraph). The mucin-producing cholangiocarcinoma tumors were classified into three types, including an intermediate type which was characterized by large cystic lesions and solid tumors that invaded the liver parenchyma (page 158, right column, first paragraph).
Muller discusses cholangiocarcinoma (CC), indicating that it is a primary liver tumor (page 2025, right column, first paragraph). Thus cholangiocarcinoma is directed to a primary liver cancer. Muller found that bromelain has potent anti-tumor activity against cholangiocarcinoma (page 2031, left column).
Ashrafi discloses microparticles comprising a gel body, wherein the gel body comprises a synthetic polymer and a drug, the microparticles have an average diameter in the range of 40 to 1500 micrometers, and the polymer is in the form of a hydrogel (paragraph [0016]). The microparticles may have any shape, and are preferably microspheres (paragraph [0032]). The diameter range of 40 to 1500 micrometers overlaps with the diameter range of instant claim 13, thereby rendering obvious the diameter limitation of instant claim 13.
Ashrafi teaches that their microparticles are for use in a method of treatment of a tumor (paragraph [0020]). Any drug which can be incorporated into the microparticles of the Ashrafi invention may find utility in their invention (paragraph [0050]). Examples of the drug include anti-tumor drugs and enzymes (paragraph [0050]). Preferred drugs are antineoplastic drugs and have chemotherapeutic properties, so they may be used in anti-tumor therapy (paragraph [0050]). Ashrafi also discloses a novel drug delivery system useful in the chemoembolotherapy of solid tumors in which the rate of drug release from the microparticles is altered when the tumor becomes hypoxic, leading to an increased release of drug as the disulfide cross-links cleave with the reductive environment of the tumor (paragraph [0021]). In particular, Ashrafi speaks of a composition which is administered to a patient in need of embolotherapy having a solid tumor, for instance a hepatocellular carcinoma, as an aqueous suspension of swollen particles containing absorbed drug (paragraph [0066]). Given the rate of drug release from the microparticles when used in chemoembolotherapy of solid tumors, then Ashrafi discloses microspheres that are adapted to elute the drug in a sustained manner following administration, meeting a claimed limitation.
Further still, Ashrafi discloses that the therapeutic active (drug) may be incorporated into the polymer matrix of the microparticles by a variety of techniques (paragraph [0064]). The active may be loaded into the polymer after it has been cross-linked (paragraph [0064]). For instance, particulate dried polymer may be swollen into a solution of therapeutic active (paragraph [0064]). Merely contacting swollen particles suspended in a continuous liquid vehicle with a solution of drug over an extended period results in the drug becoming absorbed into the body of the particles (paragraph [0064]). The microspheres of Ashrafi resulting from loading a drug into the microspheres by suspending the microspheres (which are a hydrogel) in a solution comprising the drug are directed to microspheres consisting of a hydrogel containing a solution comprising the drug.
Additionally, Example 16 of Ashrafi investigated the biocompatibility of non-drug loaded microparticles with human liver cells (paragraph [0185]). Their experiment in Example 16 showed that the HEP G2 cells survived and replicated during the incubation period in the presence of the non-drug loaded microspheres, demonstrating that the microspheres are biocompatible and have no cytotoxic effect (paragraph [0185]).
It would have been obvious to the person of ordinary skill to treat mucin-producing cholangiocarcinoma with the method of the claims of `666. One of ordinary skill in the art would have been motivated to treat mucin-producing cholangiocarcinoma with the method of the claims of `666 since mucin-producing cholangiocarcinoma (taught in Sakamoto) is directed to a mucin-producing cancer for which treatment is sought in patients. There would have been a reasonable expectation of treating mucin-producing cholangiocarcinoma since it is a mucin-producing cancer (thus directed to a disease that the claims of `666 treat) and since Muller indicates that bromelain, which is one agent administered in the method of the claims of `666, has anti-tumor activity against cholangiocarcinoma. Thus claims 1 and 9 of `666 in view of Sakamoto and Muller renders obvious a method for the treatment of a mucin-producing cancer which is a primary liver cancer.
Further still, before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have administered the bromelain and at least one mucolytic agent when practicing the method of the claims of `666 by administering a therapeutically effective amount of the microparticles of Ashrafi, specifically microspheres having an average diameter in the range of 40 to 1500 micrometers (overlapping with the range of instant claim 13, thereby rendering obvious the diameter limitation), loaded with bromelain and at least one mucolytic agent by suspending hydrogel microspheres in a solution of bromelain and at least one mucolytic agent, such that a therapeutically effective amount of these microspheres is administered to the patient when performing the method rendered obvious by the claims of `666 in view of Sakamoto, and Muller of treating mucin-producing cholangiocarcinoma (directed to a primary liver cancer). It would have been a matter of simple substitution of one form of the composition for another that is suitable for delivery to a site in a patient (e.g. animal or human body). Since Ashrafi teaches that their microparticles are used for drug delivery in the chemoembolotherapy of solid tumors such as hepatocellular carcinoma, wherein the drug incorporated into the microparticles can be anti-tumor drugs (which the bromelain and mucolytic agent of the claims of `666 are directed to since they are used for treating mucin-producing cancer) and enzymes (which the bromelain of the claims of `666 is directed to), then there would have been a reasonable expectation that Ashrafi’s microspheres would have been suitable for administering the bromelain and at least one mucolytic agent to the patient when performing the method rendered obvious by the claims of `666 in view of Sakamoto and Muller of treating mucin-producing cholangiocarcinoma. Moreover, there would have been a reasonable expectation of treating mucin-producing cholangiocarcinoma with the microspheres of Ashrafi incorporating the bromelain and at least on mucolytic agent since Ashrafi found that their microspheres are biocompatible with human liver cells (see Example 16). The microspheres of Ashrafi are directed to microspheres ‘adapted to elute the mucin-affecting protease in a sustained manner following administration’ since Ashrafi discloses a rate of drug release for their microparticles (paragraph [0021]) and elution of a drug over time from their microspheres in their examples (see Figures 12A, 12B, 19, and 21). Since the claims of `666 in view of the references renders obvious the loading of bromelain and the at least one mucolytic agent by suspending the microspheres (which are a hydrogel) in a solution of bromelain and the at least one mucolytic agent, then the references render obvious the claimed limitation ‘wherein the microspheres consist of a hydrogel containing a solution comprising the mucin-affecting proteases’ of instant claim 13.
Regarding the claimed elution time, Ashrafi discloses in their examples testing the elution of drugs from their microspheres. In Example 7, the exact amount of drug released from microspheres in two environments was calculated and shown in Figures 12A and 12B (paragraph [0153]). Figure 12A shows the elution profile up to 500 minutes, i.e. about 8 hours, and Figure 12B shows the elution profile up to about 375 minutes, i.e. about 6 hours. In Example 14, the release profile of loaded microparticles was determined and shown in Figure 19 (paragraph [0179]). Figure 19 shows the elution profile up to about 350 minutes, i.e. about 6 hours. In Example 15, the elution profile of microparticles is shown in Figure 21 (paragraph [0182]). Figure 21 shows the elution profile up to about 2750 minutes, i.e. about 46 hours. Each of these time periods of Figures 12A, 12B, 19, and 21 include periods of time falling in the claimed range of between 5 hours and 120 hours. Therefore, it would have been obvious that the bromelain elutes from the microspheres of Ashrafi over at least the time periods shown in Figures 12A, 12B, 19, and 21 of Ashrafi that encompass periods of time that fall in the range of between 5 hours and 120 hours, when practicing the method of claims 1 and 9 of `666 in view of Sakamoto, Muller, and Ashrafi.
Regarding the claimed administration, for chemoembolotherapy of solid tumors, Ashrafi teaches that their invention may be used for the local targeting of tumors by either direct intratumoural administration or delivery into the tumor vasculature via an intra-arterial route (paragraph [0021]). Ashrafi speaks of embolotherapy of a solid tumor such as a hepatocellular carcinoma (paragraph [0066]). When discussing the prior art, Ashrafi points out that embolization involves the introduction of embolic agents into the arteries feeding a tumor to starve it of its nutrients and oxygen (paragraph [0014]). For treating mucin-producing cholangiocarcinoma (directed to a primary liver cancer) in the method rendered obvious by the claims of `666 in view of Sakamoto, Muller, and Ashrafi, it would have been obvious to the person of ordinary skill in the art to administer the microspheres to the patient intra-arterially. One of ordinary skill in the art would have been motivated to do this because Ashrafi discloses that local targeting of their microparticles for chemoembolotherapy of solid tumors such as hepatocellular carcinoma can be obtained by delivery into the tumor vasculature via an intra-arterial route. Since mucin-producing cholangiocarcinoma can comprise a solid tumor (for instance, see the intermediate type of mucin-producing cholangiocarcinoma on page 158 of Sakamoto) and is a liver cancer and thus similar in site as hepatocellular carcinoma, then the skilled artisan would have reasonable expectation that chemoembolotherapy by intra-arterial route would have been suitable for treating mucin-producing cholangiocarcinoma. Therefore, claims 1 and 9 of `666 in view of Sakamoto, Muller, and Ashrafi render obvious the claimed intra-arterial administration.
As such, claims 1 and 9 of `666 in view of Sakamoto, Muller, and Ashrafi render obvious instant claims 13 (the diameter range of Ashrafi overlaps with the diameter range of instant claim 13, thereby rendering obvious the diameter limitation), and 14 (primary liver cancer).
Claims 13 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,364,286 in view of Sakamoto (J. Hep. Bil. Pancr. Surg. 1997. 4: 157-162. Previously cited), Muller (International Journal of Oncology. 2016. 48: 2025-2034. Listed on IDS filed 5/18/22), and Ashrafi (US 2014/0030350. Previously cited).
Independent claim 1 of `286 meets limitations of the instant claims since it recites a method for the treatment of disease involving mucin, the method comprising administering a therapeutically effective amount of a synergistic mucolytic composition comprising bromelain to a patient in need thereof. Independent claim 12 of `286 meets limitations the instant claims since it recites a method of disintegrating and/or solubilizing semi-hard or hard consistency mucinous material in a subject, the method comprising administering to the subject a therapeutically effective amount of a synergistic mucolytic composition comprising bromelain. Bromelain is directed to a mucin-affecting protease, specifically meeting limitations of instant claims 4 (plant derived protease) and 5. Though claims 1 and 12 of `286 also recite that the composition comprises cysteamine or a pharmaceutically acceptable salt thereof and that the mucin is characterized as having a semi-hard or hard consistency which is disintegrated by the composition which are not required by the instant claims, these are additional limitations which are wholly encompassed by the broader scope of the instant claims.
Though claims 1 and 12 of `286 do not recite a method for the treatment of a mucin-producing cancer, pseudomyxoma peritonei, cystic fibrosis or chronic obstructive pulmonary disease as recited in the instant claims, claim 5 of `286 recites that the disease involving mucin is cancer or pseudomyxoma peritonei and claim 13 of `286 recites that the subject suffers from cancer or pseudomyxoma peritonei. It would have been prima facie obvious to apply the limitations of claims 5 and 13 of `286 to the other claims of `286. In doing so, then the claims of `286 render obvious a method for the treatment of a disease involving mucin which is cancer (directed to ‘mucin-producing cancer’) and pseudomyxoma peritonei.
The claims of `286 further differ from the instant claims in that they do not recite that the therapeutically effective amount of the composition is intra-arterially, intra-abdominally or intra-cavitarily administered to the patient by administering to the patient a therapeutically effective amount of microspheres containing bromelain (directed to the claimed ‘mucin-affecting protease’) loaded therein, wherein the microspheres have a diameter of between 60 and 120 micrometers and are adapted to elute the mucin-affecting protease in a sustained manner following administration, wherein the microspheres are adapted to elute the bromelain (mucin-affecting protease) in a sustained manner over a period of time between 5 hours and 120 hours. The claims of `286 further differ from instant claim 14 in that they do not recite that the cancer (directed to mucin-producing cancer) that is treated is primary or secondary liver cancer (elected species of instant claim 14).
Sakamoto discloses cholangiocarcinomas that produce clinically recognizable mucin, known as mucin-producing cholangiocarcinoma (abstract; page 157, first paragraph). Sakamoto investigated the clinicopathologic features of tumors in ten patients with mucin-producing cholangiocarcinoma (page 157, first paragraph). The mucin-producing cholangiocarcinoma tumors were classified into three types, including an intermediate type which was characterized by large cystic lesions and solid tumors that invaded the liver parenchyma (page 158, right column, first paragraph).
Muller discusses cholangiocarcinoma (CC), indicating that it is a primary liver tumor (page 2025, right column, first paragraph). Thus cholangiocarcinoma is directed to a primary liver cancer. Muller found that bromelain has potent anti-tumor activity against cholangiocarcinoma (page 2031, left column).
Ashrafi discloses microparticles comprising a gel body, wherein the gel body comprises a synthetic polymer and a drug, the microparticles have an average diameter in the range of 40 to 1500 micrometers, and the polymer is in the form of a hydrogel (paragraph [0016]). The microparticles may have any shape, and are preferably microspheres (paragraph [0032]). The diameter range of 40 to 1500 micrometers overlaps with the diameter range of instant claim 13, thereby rendering obvious the diameter limitation of instant claim 13.
Ashrafi teaches that their microparticles are for use in a method of treatment of a tumor (paragraph [0020]). Any drug which can be incorporated into the microparticles of the Ashrafi invention may find utility in their invention (paragraph [0050]). Examples of the drug include anti-tumor drugs and enzymes (paragraph [0050]). Preferred drugs are antineoplastic drugs and have chemotherapeutic properties, so they may be used in anti-tumor therapy (paragraph [0050]). Ashrafi also discloses a novel drug delivery system useful in the chemoembolotherapy of solid tumors in which the rate of drug release from the microparticles is altered when the tumor becomes hypoxic, leading to an increased release of drug as the disulfide cross-links cleave with the reductive environment of the tumor (paragraph [0021]). In particular, Ashrafi speaks of a composition which is administered to a patient in need of embolotherapy having a solid tumor, for instance a hepatocellular carcinoma, as an aqueous suspension of swollen particles containing absorbed drug (paragraph [0066]). Given the rate of drug release from the microparticles when used in chemoembolotherapy of solid tumors, then Ashrafi discloses microspheres that are adapted to elute the drug in a sustained manner following administration, meeting a claimed limitation.
Further still, Ashrafi discloses that the therapeutic active (drug) may be incorporated into the polymer matrix of the microparticles by a variety of techniques (paragraph [0064]). The active may be loaded into the polymer after it has been cross-linked (paragraph [0064]). For instance, particulate dried polymer may be swollen into a solution of therapeutic active (paragraph [0064]). Merely contacting swollen particles suspended in a continuous liquid vehicle with a solution of drug over an extended period results in the drug becoming absorbed into the body of the particles (paragraph [0064]). The microspheres of Ashrafi resulting from loading a drug into the microspheres by suspending the microspheres (which are a hydrogel) in a solution comprising the drug are being interpreted by the Examiner as being directed to microspheres consisting of a hydrogel and a solution comprising the drug.
Additionally, Example 16 of Ashrafi investigated the biocompatibility of non-drug loaded microparticles with human liver cells (paragraph [0185]). Their experiment in Example 16 showed that the HEP G2 cells survived and replicated during the incubation period in the presence of the non-drug loaded microspheres, demonstrating that the microspheres are biocompatible and have no cytotoxic effect (paragraph [0185]).
It would have been obvious to the person of ordinary skill to treat mucin-producing cholangiocarcinoma with the method of the claims of `286. One of ordinary skill in the art would have been motivated to treat mucin-producing cholangiocarcinoma with the method of the claims of `286 since mucin-producing cholangiocarcinoma (taught in Sakamoto) is directed to a disease involving mucin which is cancer for which treatment is sought in patients. There would have been a reasonable expectation of treating mucin-producing cholangiocarcinoma since it is a disease involving mucin that is a cancer (thus directed to a disease that the claims of `286 treat) and since Muller indicates that bromelain, which is one agent administered in the method of the claims of `286, has anti-tumor activity against cholangiocarcinoma. Thus claims 1 and 12 of `286 incorporating claims 5 and 13 of `286 and in view of Sakamoto and Muller renders obvious a method for the treatment of a mucin-producing cancer which is a primary liver cancer.
Further still, before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have administered the synergistic mucolytic composition when practicing the method of the claims of `286 by administering a therapeutically effective amount of the microparticles of Ashrafi, specifically microspheres having an average diameter in the range of 40 to 1500 micrometers (overlapping with the range of instant claim 13, thereby rendering obvious the diameter limitation), loaded with bromelain and cysteamine by suspending hydrogel microspheres in a solution of bromelain and cysteamine, such that a therapeutically effective amount of these microspheres is administered to the patient when performing the method rendered obvious by claims 1 and 12 of `286 incorporating claims 5 and 13 of `286 and in view of Sakamoto and Muller of treating mucin-producing cholangiocarcinoma (directed to a primary liver cancer). It would have been a matter of simple substitution of one form of the composition for another that is suitable for delivery to a site in a patient (e.g. animal or human body). Since Ashrafi teaches that their microparticles are used for drug delivery in the chemoembolotherapy of solid tumors such as hepatocellular carcinoma, wherein the drug incorporated into the microparticles can be anti-tumor drugs (which the bromelain and cysteamine of the claims of `286 are directed to since they are used for treating cancer) and enzymes (which the bromelain of the claims of `286 is directed to), then there would have been a reasonable expectation that Ashrafi’s microspheres would have been suitable for administering the bromelain and cysteamine to the patient when performing the method rendered obvious by the claim 1 and 12 of `286 incorporating claims 5 and 13 of `286 and in view of Sakamoto and Muller of treating mucin-producing cholangiocarcinoma. Moreover, there would have been a reasonable expectation of treating mucin-producing cholangiocarcinoma with the microspheres of Ashrafi incorporating the bromelain and cysteamine since Ashrafi found that their microspheres are biocompatible with human liver cells (see Example 16). The microspheres of Ashrafi are directed to microspheres ‘adapted to elute the mucin-affecting protease in a sustained manner following administration’ since Ashrafi discloses a rate of drug release for their microparticles (paragraph [0021]) and elution of a drug over time from their microspheres in their examples (see Figures 12A, 12B, 19, and 21). Since the claims of `286 in view of the references renders obvious the loading of bromelain and cysteamine by suspending the microspheres (which are a hydrogel) in a solution of bromelain and cysteamine, then the references render obvious the claimed limitation ‘wherein the microspheres consist of a hydrogel containing a solution comprising the mucin-affecting proteases’ of instant claim 13.
Regarding the claimed elution time, Ashrafi discloses in their examples testing the elution of drugs from their microspheres. In Example 7, the exact amount of drug released from microspheres in two environments was calculated and shown in Figures 12A and 12B (paragraph [0153]). Figure 12A shows the elution profile up to 500 minutes, i.e. about 8 hours, and Figure 12B shows the elution profile up to about 375 minutes, i.e. about 6 hours. In Example 14, the release profile of loaded microparticles was determined and shown in Figure 19 (paragraph [0179]). Figure 19 shows the elution profile up to about 350 minutes, i.e. about 6 hours. In Example 15, the elution profile of microparticles is shown in Figure 21 (paragraph [0182]). Figure 21 shows the elution profile up to about 2750 minutes, i.e. about 46 hours. Each of these time periods of Figures 12A, 12B, 19, and 21 include periods of time falling in the claimed range of between 5 hours and 120 hours. Therefore, it would have been obvious that the bromelain elutes from the microspheres of Ashrafi over at least the time periods shown in Figures 12A, 12B, 19, and 21 of Ashrafi that encompass periods of time that fall in the range of between 5 hours and 120 hours, when practicing the method of claims 1 and 12 of `286 incorporating claims 5 and 13 of `286 and in view of Sakamoto, Muller, and Ashrafi.
Regarding the claimed administration, for chemoembolotherapy of solid tumors, Ashrafi teaches that their invention may be used for the local targeting of tumors by either direct intratumoural administration or delivery into the tumor vasculature via an intra-arterial route (paragraph [0021]). Ashrafi speaks of embolotherapy of a solid tumor such as a hepatocellular carcinoma (paragraph [0066]). When discussing the prior art, Ashrafi points out that embolization involves the introduction of embolic agents into the arteries feeding a tumor to starve it of its nutrients and oxygen (paragraph [0014]). For treating mucin-producing cholangiocarcinoma (directed to a primary liver cancer) in the method rendered obvious by claims 1 and 12 of `286 incorporating claims 5 and 13 of `286 and in view of Sakamoto, Muller, and Ashrafi, it would have been obvious to the person of ordinary skill in the art to administer the microspheres to the patient intra-arterially. One of ordinary skill in the art would have been motivated to do this because Ashrafi discloses that local targeting of their microparticles for chemoembolotherapy of solid tumors such as hepatocellular carcinoma can be obtained by delivery into the tumor vasculature via an intra-arterial route. Since mucin-producing cholangiocarcinoma can comprise a solid tumor (for instance, see the intermediate type of mucin-producing cholangiocarcinoma on page 158 of Sakamoto) and is a liver cancer and thus similar in site as hepatocellular carcinoma, then the skilled artisan would have reasonable expectation that chemoembolotherapy by intra-arterial route would have been suitable for treating mucin-producing cholangiocarcinoma.
Therefore, claims 1 and 12 of `286 incorporating claims 5 and 13 of `286 and in view of Sakamoto, Muller, and Ashrafi render obvious instant claims 13 (the diameter range of Ashrafi overlaps with the claimed diameter range, thereby rendering obvious the diameter limitation), and 14 (primary liver cancer).
Response to Arguments
Applicant’s arguments, filed March 4, 2026, with respect to the objection to claim 40, the rejections under 35 U.S.C. 112(b), the rejection under 35 U.S.C. 112(a) of claims 1, 4, 5, 7-14, and 35-41, the rejection under 35 U.S.C. 103 of claims 1, 4, 5, 7-12, and 39-41 as being unpatentable over Morris in view of Sakamoto, Muller, and Ashrafi, and in light of Aggarwal, the nonstatutory double patenting rejection of claims 1, 4, 5, 7-12, and 39-41 as being unpatentable over claims 1-16 of U.S. Patent No. 11,369,666 in view of Sakamoto, Muller, and Ashrafi, and in light of Aggarwal, the nonstatutory double patenting rejection of claims 1, 4, 5, 7-12, 39, and 40 as being unpatentable over claims 1-13 of U.S. Patent No. 11,364,286 in view of Sakamoto, Muller, and Ashrafi, and in light of Devereux, and the nonstatutory double patenting rejection of claims 39-41 as being unpatentable over claims 1-5, 12, and 13 of U.S. Patent No. 11,364,286 in view of Sakamoto, Muller, and Ashrafi, and further in view of Aggarwal, have been fully considered and are persuasive.
In particular, the objection has been overcome by the amendment to claim 40. The rejections under 35 U.S.C. 112(b) have been overcome by the amendments to claims 1, 13, 35, 40, and 41, and rendered moot by the cancelling of claim 39. The rejection under 35 U.S.C. 112(a) has been overcome by the amendments to claims 1, 13, and 35, and Applicant’s argument which is supported by Lewis (J. Materi. Sci.: Mater. Med. 2007. 18: 1691-1699). Specifically, Lewis teaches DC Bead microspheres composed of a poly(vinyl alcohol) (PVA) polymer hydrogel (page 1692, left column, third paragraph). These beads were loaded with doxorubicin hydrochloride (dox) by immersion of a measured volume of beads into a drug solution of the desired concentration (page 1692, right column, second paragraph). Lewis found that the beads have been shown to load the drug throughout the structure (page 1699, right column, first paragraph). DC Beads are microspheres used in the examples of the specification (e.g., Example 10 on pages 55-56 of the originally filed specification). Given that the active agent of Lewis is loaded in hydrogel microspheres (DC Beads) through immersion of the hydrogel microspheres in a solution comprising the active agent, then Lewis demonstrates that such resulting hydrogel microspheres contain a solution comprising the active agent. The rejections under 35 U.S.C. 103 and the nonstatutory double patenting rejections have been overcome by the amendment to claim 1 and Applicant’s argument that the thiol-containing agent as claimed would have broken the disulfide bonds that are essential to the microspheres of Aggarwal. Therefore, the claim objection and these rejections have been withdrawn.
Additionally, claim 13 has not been amended to require that the solution of the hydrogel of the microspheres also comprise a therapeutically effective amount of a thiol-containing mucolytic agent that reduces or disrupts disulfide bonds in mucins. Therefore, the rejection under 35 U.S.C. 103 of claims 13 and 14 and the nonstatutory double patenting rejections of claims 13 and 14 have been set forth over the same combination of prior art as cited in the last Office Action.
Conclusion
Claims 1, 4, 5, 7-12, and 35-38 are allowed.
Claims 13, 14, 40, and 41 are rejected.
Claims 40 and 41 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Sef
/SUSAN E. FERNANDEZ/Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/Primary Examiner, Art Unit 1651
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